BG108533A - Use of 2-alkoxyphenyl-substituted imidazotriazinones - Google Patents

Abstract

The invention relates to the use of known 2-phenyl substituted imidazotriazinones having short, unbranched alkyl radicals in the 9 position and cGMP-PDE-inhibiting properties for the production of medicaments to treat heart insufficiency, psoriasis, female infertility, cancer diabetes, eye diseases such as glaucoma, disorders of the stomach movement, cystic fibrosis, premature contractions, pulmonary high blood pressure, bladder diseases, prostatic hyperplasia, nitrate-induced tolerance, preeclampsia, alopecia, Parkinson's disease, pain, tinnitus or renal syndrome.

Description

The present invention relates to the use of 2alkoxyphenyl-substituted imidazotriazinones for the preparation of medicines for the treatment of heart failure, psoriasis, female infertility, cancer, diabetes, ocular diseases such as glaucoma, disorders of gastric motility, cystic fibrosis, cystic fibrosis blood pressure, bladder disease, prostate hyperplasia, nitrate-induced tolerance, preeclampsia, alopecia, Parkinson's disease, pain, tinnitus or renal syndrome.

BACKGROUND OF THE INVENTION

The patent application DE 28 11 780 describes imidazotriazinones as bronchodilators with © spasmolytic activity and cyclic adenosine monophosphate metabolizing phosphodiesterases (cAMP-PDE's, Beavo nomenclature) PDE-III and PDE nomenclature. Cyclic guanosine monophosphate inhibitory metabolizing phosphodiesterases (cGMP-PDE's, Beavo and Reifsnyder nomenclature (Trends in Pharmacol. Sci. 11, 150-155, 1990) PDE-I, PDE-II and PDE-V) have not been described. It will use compounds that contain a sulfonamide group in the aryl moiety at the 2-position. Further, FR 22 13 058, CH 59 46 71, DE 22 55 172, DE 23 64 076 and EP 000 9384 describe imidazotriazinones which have no substituted aryl residue in the 2-position and also describe them as bronchodilators with cAMP- PDE inhibitory action.

WO 94/28902 discloses pyrazolopyrimidinones which are suitable for the treatment of impotence.

WO 99/24433 and WO 99/67244 describe imidazotriazinones which are suitable for the treatment of impotence.

To date, 11 © phosphodiesterases of different specificity with cyclic nucleotides cAMP and cGMP have been described in the literature (cf. Fawcett et al., Proc. Nat. Acad. Sci. 97 (7), 3072-3077 (2000)). Cyclic guanosine 3 ', 5-monophosphate phosphodiesterases (cGMPPDE's) metabolizers are PDE-1, 2, 5, 6, 9,10,11. The compounds according to the invention are potent phosphodiesterase inhibitors 5. The differential expression of phosphodiesterases in different cells, tissues and organs, as well as the differentiated subcellular localization of these enzymes, make possible, in conjunction with the selective inhibitors according to the invention, selectively increase the specific concentration of the cells. , tissues and organs, thus addressing different cGMP regulated processes. This is particularly expected when the synthesis of cGMP is increased under certain physiological conditions. For example, during sexual stimulation by the neural pathway, nitrous monoxide is released into the vessels of Corpus Cavernosum and thus increases the synthesis of cGMP. This causes the vessels that supply blood to the Corpus Cavernosum to be greatly expanded and an erection is caused. Therefore, cGMP inhibitors metabolizing PDE's should be particularly suitable for the treatment of erectile dysfunction.

An increase in cGMP concentration can lead to healing, antiplatelet, antithrombotic, antiproliferative, anti-vasospastic, vasodilating, natriuretic and diuretic effects and may affect the transmission of excitement to the central nervous system and thus memory power. Short-term and long-term modulation of vascular and cardiac inotropy, cardiac rhythm, and cardiac tolerability may be affected (J. C. Stoclet, T. Keravis, N. Komas, and S. Lugnier, Exp.

Opin. Invest. Drugs (1995), 4 (11), 1081-1100).

SUMMARY OF THE INVENTION

The present invention relates to the use of compounds of general formula (I)

(I) in which

R ¹ stands for methyl or ethyl,

R ² means ethyl or propyl,

R ³ and R ⁴ are the same or different and represent a straight or branched alkyl chain of up to 5 carbon atoms which is optionally substituted up to two times, the same or different, by hydroxy or methoxy, or

R ³ and R ⁴ together with the nitrogen atom form a piperidinyl-, morpholinyl-, thiomorpholinyl-ring or a residue of formula _m <~ 5 -N NR ⁵

WHEREIN

R ⁵ represents hydrogen, formyl, acyl or alkoxycarbonyl of up to 3 carbon atoms, or represents straight or branched alkyl of up to 3

carbon atoms which are optionally one or two times the same or different, substituted by hydroxy, carboxyl, straight chain or branched alkoxy or alkoxycarbonyl of up to 3 carbon atoms or with groups of the formula - (D) _a NR ⁶ R ⁷ or -P (O) (OR ⁸ ) (OR ⁹ ) in which a represents the number 0 or 1,

D represents a group of formula -CO,

R ⁶ and R ⁷ denote the same or different hydrogen or methyl,

R ⁸ and R ⁹ denote the same or different hydrogen, methyl or ethyl, or

R ⁵ is cyclopentyl, and the heterocycles formed under the R ³ and R ⁴ heterocycles are optionally one to two times the same or different, optionally also geminally substituted with hydroxy, formyl, carboxyl, acyl or alkoxycarbonyl, respectively up to 3 carbon atoms or with groups of the formulas -P (O) (OR ¹⁰ ) (OR ¹¹ ) or - (CO) _b NR ¹² R ¹³ in which

R ¹⁰ and R ¹¹ are the same or different and represent hydrogen, methyl or ethyl, b means the number 0 or 1, and

R ¹² and R ¹³ are identical or different and denote hydrogen or methyl, and / or indicated for R ³ and R ⁴ form together with the nitrogen heterocycles, in certain cases, are substituted with © straight chain or branched alkyl having up to 3 carbon atoms, which is in one case two to one, the same or different, substituted with hydroxy, carboxyl or a residue of formula P (O) OR ¹⁴ OR ¹⁵ in which

R ¹⁴ and R ¹⁵ are identical or different and denote hydrogen, methyl or ethyl, and / or indicated for R ³ and R ⁴ form together with the nitrogen atom heterocycles in given case are substituted with a nitrogen atom bonded at piperidinyl or pyrrolidinyl, © and

R ¹⁶ means ethoxy or propoxy, and their salts, hydrates and / or solvates, for the preparation of medicines for the treatment of heart failure, psoriasis, female infertility, cancer, diabetes, eye diseases such as glaucoma, disorders of gastric motility, cystic fibrosis, premature pain, pulmonary high blood pressure, bladder disease, prostate hyperplasia induced by nitrate tolerance, preeclampsia, alopecia, Parkinson's disease, pain, tinnitus or renal syndrome.

• · · · ·

Particularly preferred according to the present invention is the use of the following compounds:

for the preparation of drugs for the treatment of heart failure, psoriasis, female infertility, cancer, diabetes, eye diseases such as glaucoma, disorders of gastric motility, cystic fibrosis, premature pain, pulmonary high blood pressure, diseases of the bladder, bladder, bladder disease nitrate-induced tolerance, preecompression, alopecia, Parkinson's disease, pain, tinnitus or renal syndrome.

© Physiologically safe salts are preferred within the invention. Salts of the compounds of the invention with inorganic and organic acids may be physiologically reliable salts. Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids, eg acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, tartaric acid, preferred acid are preferred. benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically reliable salts may also be metal or ammonium salts of the compounds of the invention. Sodium, potassium, magnesium or calcium salts, as well as ammonium salts derived from ammonia or organic amines such as ethylamine, di- respectively triethylamine, di- respectively triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginylamine, arginylamine or arginine-2-arginine .

• · · · · · · · · ·

The compounds of the invention, in particular salts, may be in the form of hydrates. In the context of the invention, hydrates are those compounds which contain water in the crystal. Such compounds may contain one or more, typically 1 to 5, equivalent of water. The hydrates are prepared, for example, by allowing the corresponding compound to crystallize from water or a water-containing solvent.

© The solvates of the compounds of the invention are the stoichiometric compositions of the compounds or their salts with a solvent.

An acyl residue of 1 to 3 carbon atoms means, for example, formyl, acetyl or ethylcarbonyl within the scope of the invention.

A straight or branched alkoxy moiety of 1 to 3 carbon atoms means within the scope of the invention methoxy, ethoxy n-propoxy or isopropoxy.

An alkoxycarbonyl moiety having 1 to 3 carbon atoms U means within the framework of the invention methoxycarbonyl or ethoxycarbonyl.

A straight or branched alkyl radical having 1 to 5 or 1 to 3 carbon atoms means, for example, methyl, ethyl, η-propyl, isopropyl, tert, within the invention. butyl, n-pentyl. Straight or branched moieties having 1 to 4 or 1 to 3 carbon atoms are preferred.

Halogen within the scope of the invention generally means fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred. Fluorine and chlorine are particularly preferred.

• · · · · · · · · · ·

Another embodiment of the invention relates to the use according to the invention of compounds of general formula (I) in which the residues R ¹⁶ and -SO ₂ NR ³ R ⁴ are in a para-position relative to each other in the phenyl ring and R ¹ , R ² , R ³ , R ⁴ and R ¹⁶ have the meaning indicated above.

Another embodiment of the invention relates to the use according to the invention of compounds of general formula (Ia)

Ca) wherein R ¹ , R ² , R ³ , R ⁴ and R ¹⁶ are as defined above, and their salts, hydrates and / or solvates.

According to the invention it is preferred to use the following compounds:

2- [2-Ethoxy-5- (4-methyl-piperazine-1-sulfonyl) 'phenyl] -

5,7-dimethyl-3H-imidazo [5,1-N- [1,2,4] triazin-4-one;

2- [2-ethoxy-5- (4-hydroxyethylpiperazine-1-sulfonyl) phenyl] -5,7-dimethyl-3H-imidazo [5,1-D] - [1,2,4] triazin-4-one ;

2- [2-ethoxy-5- (4-hydroxypiperidine-1-sulfonyl) phenyl] -5,7-dimethyl-3H-imidazo [5,1- [1,2,4] triazin-4-one;

2- [2-ethoxy-5- (4-hydroxymethylpiperidine-1-sulfonyl) phenyl] -5,7-dimethyl-3H-imidazo [5,1-N- [1,2,4] triazin-4-one;

.:. : · · ·

2- [2-ethoxy-5- (3-hydroxypyrrolidine-1-sulfonyl) phenyl] -5,7-dimethyl-3H-imidazo [5D-D] - [1 _/ 2,4] triazin-4-one;

4-Ethoxy-N-ethyl-N- (2-hydroxyethyl) -3- (5,7-dimethyl-4oxo-3,4-dihydro-imidazo [5,1-N] - [1 / 2,4] triazine -2-yl) benzenesulfonamide;

N, N-diethyl-4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5,1-N- [1,2,4] triazin-2-yl) benzenesulfonamide;

is 2- [2-ethoxy-5- (4- (2-pyrimidinyl) -piperazine-1-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5,1- [1,2,4] triazin-4-one;

2- [2-ethoxy-5- (morpholine-4-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5D-N - [1,2,4] triazin-4-one;

2- [2-ethoxy-5- (1,4-dioxa-6-azaspiro [4.4] nonan-6sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5D-D] - [1,2, 4] triazin-4-one;

N, N-bis- (2-methoxyethyl) -4-ethoxy-3- (5,7-dimethyl-4-oxo)

3,4-dihydroimidazo [5D-N- [1,2,4] triazin-2-yl) -1H-benzenesulfonamide;

N- (3-isoxazolyl) -4-ethoxy-3- (5,7-dimethyl-4-oxo-3,4-dihydroimidazo [5D-N- [1,2,4] triazin-2-yl) benzenesulfonamide;

2- [2-ethoxy-5- (2H-butoxycarbonylaminomethylmorpholine-4-sulfonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5D-L [1,2,4] triazin-4-one;

2- [2-ethoxy-5- (4-phenylpiperazine-1-sulfonyl) -phenyl] -

5,7-dimethyl-3H-imidazo [5D-T] - [1,2,4] triazin-4-one;

2- [2-ethoxy-5- (3-hydroxy-3-methoxymethylpyrrolidin-1C7ylphonyl) -phenyl] -5,7-dimethyl-3H-imidazo [5D] - [1,2,4] triazin-4-one ;

2- [2-ethoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -5methyl-7-propyl-3H-imidazo [5,1- [1- _l 2,4] triazin-4 -one;

2- [2-ethoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -5methyl-7-propyl-3H-imidazo [5,1-N- [1,2,4] triazin-4 -one lactate;

2- [2-ethoxy-5- (4-methyl-piperazine-1-sulfonyl) -phenyl] -5methyl-7-propyl-3H-imidazo [5,1-D] - [1,2,4] triazine- 4-one hydrochloride;

2- [2-ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5 _/ 1-N- [1 _/ 2,4] triazine -4-one;

2- [2-ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5methyl-7-propyl-3H-imidazo [5,1-N- [1,2,4] triazin-4 -one hydrochloride;

2- [2-ethoxy-5- (4-methyl-1-amino-piperazine-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5D - N - [1 _/ 2,4] triazin-4one;

2- [2-ethoxy-5- (4-hydroxyethyl-1-amino-piperazine-1-sulfonyl) -phenyl-5-methyl-7-propyl-3H-imidazo [5,1-L- [1,2,4] triazin-4-one;

N, N-bishydroxyethylaminoethyl-4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1] - [1,2,4] triazin-2-yl) -benzenesulfonamide ;

2- [2-ethoxy-5- (4-dimethoxyphosphorylmethyl-piperazine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5 _/ 1-D] - [1,2,4] triazine- 4-it;

2- [2-ethoxy-5- (4-diethoxyphosphorylmethyl-piperidine-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-1 ^: ] - [1,2,4] triazine -4-one;

2- [2-ethoxy-5- (4-hydroxy-piperidine-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-D] - [1,2,4] triazine -4H;

2- {2-ethoxy-5- [4- (2-hydroxy-ethyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5,1- | - [1.2.4 ] triazin-4-one;

2- {2-ethoxy-5- [4- (2-hydroxy-ethyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5,1- | - [1.2.4 ] triazin-4-one hydrochloride;

2- {2-ethoxy-5- [4- (2-hydroxy-propyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5,10e [1,2,4] triazin-4-one;

N-allyl-4-ethoxy-1 N- (2-hydroxy-ethyl) -3 (5-methyl-4-oxo-

7-propyl-3,4-dihydro-imidazo [5,1-D] - [1,2,4] triazin-2-yl) benzenesulfonamide;

N-ethyl-4-ethoxy-1 N- (2-hydroxy-ethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1- [1- 2,4] triazin-2-yl) benzenesulfonamide;

N-diethyl-4-ethoxy-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,10- [1,2,4] triazin-2-yl) benzenesulfonamide;

N- (2-methoxyethyl) -3- (5-methyl-4-oxo-7-propyl) amide

3,4-dihydro-imidazo [5,10- [1,2,4] triazin-2-yl) -4-ethoxybenzenesulfonic acid;

1 '1- (2-1', 1'-dimethylethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-N- [1,2, 1] 4] triazin-2-yl) -4ethoxy-benzenesulfonic acid;

N- [3- (1-morpholino) propyl] -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,10- [1,2,4] triazine-2 amide) -yl) -4ethoxy-benzenesulfonic acid;

N- {3- [1- (4-Methyl) piperazino] -propyl} -3- (5methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,10- [1.2.4] amide ] triazin-2-yl) -4-ethoxy-benzenesulfonic acid;

··· · ·· * · ί · * ·· *!

2- {2-Ethoxy-5- [4- (2-methoxy-ethyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5,1-d] [1,2 , 4] triazin-4-one;

2- {2-ethoxy-5- [4- (2-N, N-dimethyl-ethyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5,1-N- [1,2,4] triazin-4-one;

2- {2-ethoxy-5- [4- (3- {N-dimethyl-propyl) -piperazine-1-sulfonyl] -phenyl} -5-methyl-7-propyl-3H-imidazo [5,1-N] [ 1,2,4] triazin-4-one;

2- [2-ethoxy-5- (4-dioxolano-piperidine-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-1> [1,2,4] triazine- 4on;

2- [2-ethoxy-5- (4- (5-methyl-4-furoksankarbonil) piperazine-1-sulfonyl) -phenyl] -5-metil7-propyl-ZNMMHfla3o [5 _z lf] - [l, 2 _z 4 ] TpMa3MH-4-OH;

2- {2-ethoxy-5- [4-acetyl-piperazine-1-sulfonyl] -phenyl} -

5-Me ™ n-7-nponMn-3H-MMMfla3o [5,1f] - [1 _z 2 _z 4] TpMa3kiH-4-OH;

2- {2-ethoxy-5- [4-formyl-piperazine-1-sulfonyl] -phenyl} N 5-methyl-7-naphthyl-3H-MMMfluoro [5 _z 1f] - [1 _z 2 _z 4] TpMa 3 HH- 4-OH;

2- [2-ethoxy-5- (3-butylsidonimine) -1-sulfonyl) -phenyl] 5-methyl-7-propyn-3H-MMHfla3O [5 _z 1f] - [1 _z 2 _z 4] TpMa3HH-4- OH;

5-methyl-2- [5- (4-methyl-piperazine-1-sulfonyl) -2-propoxy-phenyl] -7-propyl-3H-imidazo [5,1-1 ^: ] - [1,2 _/ 4] triazine -4H;

5-methyl-2- [5- (4-methyl-piperazine-1-sulfonyl) -2-propoxy-phenyl] -7-propyl-3H-imidazo [5,1-D] - [1,2 _/ 4] triazine- 4on hydrochloride;

2- [5- (4-Hydroxypiperidine-1-sulfonyl) -2-propoxyphenyl] -5-methyl-7-propyl-3H-imidazo [5 _/ 1-D] - [1,2 _/ 4] triazin-4one;

2- [5- (4-Hydroxymethylpiperidine-1-sulfonyl) -2-propoxy-phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-D] - [1,2,4] triazine-4- he;

2- {5- [4- (2-hydroxyethyl) -piperazine-1-sulfonyl] -2-propoxy-phenyl} -5-methyl-7-propyl-3H-imidazo [5,1-N- [1,2,4 ] triazin-4-one;

1 \ 1- (1,1-Dioxotetrahydro-1-thiophen-3-yl) -3- (5methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5, Ι-ΠΟ [1 , 2,4] triazin-2-yl) -4-propoxy-benzenesulfonic acid;

N- (2-dimethylaminoethyl) -N-methyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-] - [1,2,4] triazine- amide 2yl) -4-propoxy-benzenesulfonic acid;

3- (5-Methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5D-N- [1D4] triazin-2-yl) -1'- (3-morpholine-4-) amide yl-propyl) -4-propoxy-benzenesulfonic acid;

N, N-bis- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-N- [1,2,4] triazine- amide) 2-yl) -4-propoxy-benzenesulfonic acid;

N- (3-hydroxybenzyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-N- [1,2,4] triazin-2-yl) amide ) -4-propoxy-benzenesulfonic acid;

N-ethyl-N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-N- [1,2,4] triazine- amide 2-yl) -4-propoxy-benzenesulfonic acid;

N- (3-Ethoxypropyl) -3- (5-methyl-4-oxo-7-propyl) amide

3,4-dihydro-imidazo [5,1- [1,2,4] triazin-2-yl) -4-propoxybenzenesulfonic acid;

2- [5- (4-Hydroxypiperidine-1-sulfonyl) -2-propoxyphenyl] -5-methyl-7-propyl-3H-imidazo [5 _/ 1-N- [1,2,4] triazin-4one;

• 3- (5-Methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5,1-3H-1,2,4] triazin-2-yl) -4-propoxy-1 N-pyridine amide - 4-yl-benzenesulfonic acid;

N, N-diethyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1- [1,2,4] triazin-2-yl) amide -4-propoxybenzenesulfonic acid;

1- [3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1G] - [1,2,4] triazin-2-yl) -4-propoxy-benzenesulfonyl ] Piperidine-4-carboxylic acid;

5-Methyl-2- [5- (morpholine-4-sulfonyl) -2-propoxy-phenyl] N-propyl-3H-imidazoEZD-NHC2-triazin-1-one;

amide of N- (2-hydroxyethyl) -N-methyl-3- (5-methyl-4-oxo-7propil-S _l 4-dihydro-imidazo [5,1-f] - [1,2,4] triazine -2-yl) -4-propoxy-benzenesulfonic acid;

N- (2-Hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl 3 N-dihydro-imidazo [5,1-1] - [1,2,4] triazin-2-yl) amide -4-proxy-1-propyl-benzenesulfonic acid;

amide of N- [2- (3 ₇ 4-dimethoxy-phenyl) ethyl] -N-methyl-3- (5f methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-f ] - [1,2,4] triazin-2-yl) -4-propoxy-benzenesulfonic acid;

N-allyl-N- (2-hydroxyethyl) -3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-N- [1,2,4] triazine- amide 2-yl) -4-propoxy-benzenesulfonic acid;

N-allyl-N-cyclopentyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-N- [1,2,4] triazin-2-yl) amide -4-propoxy-benzenesulfonic acid;

N-Allyl-1 N-ethyl-3- (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1- [1,2,4] triazin-2-yl) amide -4-propoxybenzenesulfonic acid;

• *

2- [2-ethoxy-4-methoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-N- [1,2,4] triazin-4one;

2- {2-Ethoxy-5- [4- (2-hydroxyethyl) -piperazine-1-sulfonyl] -4-methoxy-phenyl} -5-methyl-7-propyl-3H-imidazo [5,1 <H1,2,4] triazin-4-one;

4-Ethoxy-N-ethyl-N- (2-hydroxyethyl) -2-methoxy-5 (5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-N- [1 _/ 2,4] © triazin-2-yl) -benzenesulfonic acid;

4-Ethoxy-1- {1- (4-ethoxyphenyl) -2-methoxy-5- (5methyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1] - [1, 2,4] triazin-2-yl) -benzenesulfonic acid;

4-Ethoxy-1'-ethyl-1'- 1- (2-hydroxyethyl) -3- (5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1 <H1,2] amide , 4] triazin-2-ylbenzenesulfonic acid;

N- (2-methoxyethyl) -3- (5-ethyl-4-oxo-7-propyl) amide

3,4-dihydro-imidazo [5,1-D] - [1,2,4] triazin-2-yl) -4-ethoxybenzenesulfonic acid;

N, N-bis- (2-methoxyethyl) -3- (5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5,1-C- [1,2,4] triazine] amide -2-yl) ethoxy-benzenesulfonic acid;

2- [5- (4-Hydroxypiperidine-1-sulfonyl) -2-ethoxyphenyl] 5-ethyl-7-propyl-3H-imidazo [5,1-N- [1,2,4] triazin-4-one;

2- [5- (4-hydroxymethylpiperidine-1-sulfonyl) -2-ethoxyphenyl] -5-ethyl-7-propyl-3H-imidazo [5,1-N- [1,2,4] triazin-4one;

2- {2-ethoxy-5- [4- (2-hydroxyethyl) -piperazine-1-sulfonyl] -phenyl} -5-ethyl-7-propyl-3H-imidazo [5,1-D] - [1,2, 4] triazin-4-one;

• 4 ·

2- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) -phenyl] -5ethyl-7-propyl-3H-imidazo [5,1-N- [1,2,4] triazin-4-one ;

2- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) -phenyl] -5ethyl-7-propyl-3H-imidazo [5,1-N- [1,2,4] triazin-4-one hydrochloride;

3- (5-Ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo [5D-T] - [1 / 2,4] triazin-2-yl) -1 \ 1- (3 -morpholin-4-ylpropyl) -4ethoxy-benzenesulfonic acid;

N- (2-hydroxyethyl) -3- (5-ethyl-4-oxo-7-propyl) amide

3,4-dihydro-imidazo [5,1-D] - [1,2,4] triazin-2-yl) -4-ethoxy-N-propyl-benzenesulfonic acid;

2- [2-ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5methyl-7-propyl-3H-imidazo [5,1-d] - [1,2,4] triazine- 4-one hydrochloride trihydrate;

2- [2: ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl] -5methyl-7-propyl-3H-imidazo [5,1T] - [1,2,4] triazine-4- it is dihydrochloride.

The compounds of the invention may be prepared according to the description in WO 99/24433, the disclosure of which is hereby specifically taken into account.

The compounds of the invention are potential inhibitors of metabolic c-GMP phosphodiesterase 5. This results in an increase in c-GMP. The differential expression of phosphodiesterases in different cells, tissues and organs, as well as the differentiated subcellular localization of these enzymes, make it possible, by means of the selective inhibitors of the invention, to selectively address different processes regulated by c-GMP.

In addition, the compounds of the invention enhance the action of substances such as EDRF (* Endothelium derived relaxing factor), ANP (atrial natriuretic peptide), nitro vasodilators and all other substances which, in other ways, as phosphodiesterase inhibitors, increase the concentration of c -GMP.

Therefore, the compounds of general formula (I) according to the invention are suitable for the prevention and / or treatment of diseases in which the increase in c-GMP concentration is curative, i.e. diseases that are related to c-GMP-regulated processes (commonly referred to in English simply as c-GMP-related diseases). The present invention relates to heart failure, psoriasis, female infertility, cancer, diabetes, eye diseases such as glaucoma, disorders of gastric motility, cisgic fibrosis, premature pain, pulmonary high blood pressure, bladder prostatic disease, bladder prostatic disease, nitrates tolerance, preeclampsia, alopecia, Parkinson's disease, pain, tinnitus or renal syndrome.

U Temporary or prolonged damage to the eyes may occur due to narrowing of the blood vessels and, consequently, insufficient supply of nutrients to the eye. For example, this may be paralleled by high intraocular pressure, one of the causes of glaucoma (compare: eg Van de Voorde, J. Invest. Ophtal. & Vis. Sci. 39 (9): 1642-1646 (1998)). Delayed progression of glaucomatous optic neuropathy has been reported with systemic uptake of a NO donor, which could be due to dilation of blood vessels in the eye (compare: Afshari, Invest. Ophtalmol. Vis. Sci. 38 (Suppl.): S277 (1997); Grunwald, British J. Ophtal. 83 (2): 162-167 (1999).

Inhibitors of c-GMP PDE lead - as described above analogously to NO donors - to increase the c-GMP level and thus may cause, among other things, vasodilation of blood vessels in the eye and thus be used to treat glaucoma .

In principle, the compounds of formula (I) may also be used for the treatment of other diseases of the eye, for example for the treatment or prophylaxis of central O retinal or posterior ciliary arterioplasia, central retinal venous occlusion, ocular neuropathy such as anterior ischemic optic neuropathy, or glaucoma optic neuropathy and macular degeneration.

The activity of the compounds of formula (I) as phosphodiesterase inhibitors (PDEs) is described in WO 99/24433, the contents of which are given particular attention.

The active substances as well as their physiologically safe salts (eg hydrochlorides, maleates or lactates) can be converted by known means into conventional formulations such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert , non-toxic, pharmaceutically suitable carriers or solvents. The therapeutically effective compound is, respectively, at a concentration of 0.5 to 9 wt. % of total mixture, i. in quantities sufficient to reach the set dosage level.

The formulations are prepared, for example, by mixing the active substances with solvents and / or carriers, optionally using emulsifying agents and / or dispersing agents, for example in the case of using water.

as organic solvent, organic solvents may be used as auxiliary solvents in some cases.

Administration is by conventional means preferably oral, transdermal or parenteral eg perlingual, buccal, intravenous, nasal, rectal or inhalation.

When used by humans by oral administration, dosages of 0.001 to 50 mg / kg are preferably administered, preferably 0.01 mg / kg to 0.5 mg / kg.

However, in some cases, it may be necessary to deviate from the indicated amounts, depending on the body weight and the method of administration, the individual tolerability of the medication, the type of preparation and the time and interval, respectively, at which the administration takes place. Thus, in some cases it may be less than the minimum amount indicated above, while in other cases the above limit should be exceeded. When larger quantities of q are taken, it may be advisable to distribute them to several intakes throughout the day.

The compounds of the invention are also suitable for use in veterinary medicine. For use in veterinary medicine, the compounds or their non-toxic salts may be administered by appropriate formulations in accordance with customary veterinary practice. The veterinarian can determine how to use and dosage according to the type of animal being treated.

Claims (3)

Use of 2-phenyl-substituted imidazotriazinones of the general formula (I) in which R ¹ stands for methyl or ethyl, R ² means ethyl or propyl, R ³ and R ⁴ are the same or different and denote a straight or branched alkyl chain of up to 5 carbon atoms which is optionally substituted up to twice, uniformly or differently, by hydroxy or methoxy, or R ³ and R ⁴ together with the nitrogen atom form a piperidinyl-, morpholinyl-, thiomorpholinyl-ring or a residue of the formula wherein R ⁵ represents hydrogen, formyl, acyl or alkoxycarbonyl of up to 3 carbon atoms, or represents a straight or branched alkyl of up to 3 carbon atoms, which is optionally substituted by hydroxy, carboxyl, straight or branched, in one or two cases, the same or different or branched alkoxy or alkoxycarbonyl of up to 3 carbon atoms or of groups of the formula - (D) ₃ NR ⁶ R ⁷ or -P (O) (OR ^S ) (OR ⁹ ) in which a represents the number 0 or 1, D represents a group of formula -CO, R ⁶ and R ⁷ denote the same or different hydrogen or methyl, R ⁸ and R ⁹ denote the same or different hydrogen, methyl © or ethyl, or R ⁵ represents cyclopentyl, and the heterocycles formed by the nitrogen atom under R ³ and R ^4, optionally one to two times, identical or different, optionally also geminally substituted with hydroxy, formyl, carboxyl, acyl or alkoxycarbonyl, respectively up to 3 carbon atoms or with groups of the formulas P (OXOR ¹⁰ XOR ⁿ ) or - (CO) _b NR ¹² R ¹³ in which u R ¹⁰ and R ¹¹ are the same or different and denote hydrogen, methyl or ethyl, b means the number 0 or 1, and R ¹² and R ¹³ are identical or different and denote hydrogen or methyl, and / or indicated for R ³ and R ⁴ form together with the nitrogen heterocycles, in certain cases, are substituted with straight or branched alkyl having up to 3 carbon atoms which optionally, one to two, identical or different, is substituted by hydroxy, carboxyl or a residue of formula P (O) OR ¹⁴ OR ¹⁵ in which R ¹⁴ and R ¹⁵ are identical or different and denote hydrogen, methyl or ethyl, and / or indicated for R ³ and R ⁴ form together with the nitrogen heterocycles, in certain cases, are substituted at the nitrogen atom by a piperidinyl or pyrrolidinyl, and R ¹⁶ means ethoxy or propoxy, and salts, hydrates and / or solvates thereof, for the preparation of medicines for the treatment of heart failure, psoriasis, female infertility, cancer, diabetes, eye diseases such as glaucoma, disorders of gastric motility, cystic fibrosis, premature pain, pulmonary high blood pressure, bladder disease, prostate hyperplasia induced by nitrate tolerance, preeclampsia, alopecia, Parkinson's disease, pain, tinnitus or renal syndrome. Use according to claim 1 of compounds of general formula (1a) wherein R ¹ , R ² , R ³ , R ⁴ and R ¹⁶ have the meanings given in claim 1, and salts, hydrates and / or solvates thereof. Use of 2-phenyl-substituted imidazotriazinones according to claim 1 or 2 with the following structures: • · • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • · · · · For the preparation of drugs for the treatment of heart failure, psoriasis, female infertility, cancer, diabetes, eye diseases such as glaucoma, disorders of gastric motility, cystic fibrosis, premature pain, pulmonary high blood pressure, bladder disease, prostate hyperplasia induced by nitrate tolerance, preeclampsia, alopecia, Parkinson's disease, pain, tinnitus or renal syndrome.